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Research Articles

Novel antagonists of the thioesterase domain of human fatty acid synthase

Cancer Research Center and Center on Proteolytic Pathways, Burnham Institute for Medical Research, La Jolla, California

Requests for reprints: Jeffrey W. Smith, Cancer Research Center and Center on Proteolytic Pathways, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: 858-646-3100; Fax: 858-713-9921. E-mail: jsmith{at}burnham.org

Abstract

Fatty acid synthase (FAS) is up-regulated in a wide range of cancers and has been recently identified as a potential therapeutic target. Indeed, previous research has shown that inhibition of FAS with active site-modifying agents can block tumor cell proliferation, elicit tumor cell death, and prevent tumor growth in animal models. Here, we use a high-throughput fluorogenic screen and identify a novel pharmacophore, 5-(furan-2-ylmethylene) pyrimidine-2,4,6-trione, which inhibits the thioesterase domain of FAS. The novel antagonists are competitive inhibitors of the thioesterase domain, inhibit de novo fatty acid synthesis, and elicit FAS-dependent tumor cell death. This set of novel FAS antagonists provides an important pharmacologic lead for further development of anticancer therapeutics. [Mol Cancer Ther 2007;6(7):2120–6]

Grant support: NIH grant AI055789 (R. Liddington), CA108959 (J.W. Smith), AI061139 (A. Strongin), and CA030199 (K. Vuori).

¹ Recent studies have generated questions about the origin of this cell line.

² http://www.pannanugget.com

Received 3/16/07; revised 5/ 3/07; accepted 5/25/07.